Substituted 2-(2-pyridinylmethylsulfinyl)-1H-benzimidazoles such as for example lansoprazole, omeprazole, pantoprazole and rabeprazole including their stereoisomers are inhibitors of gastric acid secretion. Some compounds useful as prodrugs of proton pump inhibitors are disclosed in U.S. Pat. No. 6,559,167.
These compounds and structurally related compounds have a stereogenic center at sulfur and therefore exist as two optical isomers. The resolution processes of racemates of these compounds were, for example, disclosed in DE 4035455 and WO 94/27988. According to these processes chiral ether such as fenchyloxymethyl or chiral acyloxy methyl group such as mandeloyl—is introduced into the 1-position of benzimidazole ring of racemic sulfoxide compound to obtain a diastereomeric mixture, diastereomers are then separated and desired isomer is liberated from a separated diastereomer. The process requires either the preparation of fenchyloxymethyl chloride and then reaction with the racemic compound; or introduction of chloromethyl group on 1-position of benzimidazole ring, followed by reaction with the chiral auxiliary. We found that these intermediates are difficult to prepare and involve in many steps.
U.S. Pat. No. 7,176,319 B2 disclosed a resolution of racemic sulfoxide compounds using chiral camphoursulfonyl chloride.
U.S. Pat. Nos. 5,948,789 and 7,365,206 B2 disclosed stereoselective oxidation methods for the preparation of chiral substituted 2-(2-pyridinylmethylsulfinyl)-1H-benzimidazoles.
International Patent Publication No. WO 2008/004245 and CN 1087739 disclosed processes for preparation of an optically pure or optically enriched enantiomer of a sulphoxide compound using R- or S-1,1′-bi-2-naphthol (R- or S-BINOL).
Lansoprazole, chemically 2-[[[3-methyl-4-(2,2,2-trifluoro-ethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole were disclosed in European Patent No. 0174726 and U.S. Pat. No. 4,628,098. Lansoprazole was a well-known gastric acid secretion inhibitor, and was useful for prophylaxis and therapy of digestive ulcers (e.g. gastric ulcer, duodenal ulcer) and gastritis. The generic name dexlansoprazole is marketed by Takeda Pharms under the brand KAPIDEX.
U.S. Pat. No. 6,462,058 disclosed a crystal of R-lansoprazole and its use as an anti-ulcer agent. U.S. Pat. Nos. 6,462,058 and 6,664,276 and International Patent Publication No. WO 00/78745 all described the synthesis of a crystal of R-lansoprazole. Exemplary methods for such synthesis include:
a) Optical resolution of substituted 2-(2-pyridinylmethylsulfinyl)-1H-benzimidazoles by a fractional crystallization method, which includes forming a salt between a racemate and an optically active compound (for example, (+)-mandelic acid, (−)-mandelic acid, (+)-tartaric acid, (−)-tartaric acid, camphoursulfonyl chloride, or camphanic acid). The diastereoisomeric salt is separated by fractional crystallization and then subjected to a neutralization process to give a free optical isomer.
b) The chiral column method includes a method in which a racemate or a salt is applied to a column for optical isomer separation. In liquid chromatography, for example, optical isomers are separated by adding the racemate to a chiral column (such as the Daicel® series (produced by Daicel Chemical Industries, Ltd.), and eluting in water, a buffer (for example, a phosphate), an organic solvent (for example, hexane, ethanol, methanol, isopropanol, acetonitrile, triethylamine, or mixtures thereof) or mixtures of the foregoing.
c) The asymmetric oxidation process includes subjecting substituted 2-(2-pyridinylmethylsulfinyl)-1H-benzimidazoles to an asymmetric oxidation to obtain enantiomer of substituted 2-(2-pyridinylmethylsulfinyl)-1H-benzimidazoles, followed by crystallizing the resultant isomer.
The optical resolutions of (R)-(+)-lansoprazole from racemic lansoprazole were disclosed in International Patent Application No. WO 2009/087672.
We have found that the use of various chiral acids such as chiral camphoursulfonyl chloride, camphanic acid, (+)-mandelic acid, (−)-mandelic acid, (+)-tartaric acid and (−)-tartaric acid for the resolution of substituted 2-(2-pyridinylmethylsulphinyl)-1H-benzimidazoles does not result in the separation of enantiomers.
We have discovered a novel process for optical resolution of substituted 2-(2-pyridinylmethylsulphinyl)-1H-benzimidazoles either as a single enantiomer or in an enantiomerically enriched form. The object of the present invention is to provide an improved and commercially viable process for optical resolution of substituted 2-(2-pyridinylmethylsulphinyl)-1H-benzimidazoles. The process of the invention can be applied to obtain an enantiomer of substituted 2-(2-pyridinylmethylsulphinyl)-1H-benzimidazoles with an optical purity to the extent of 100%.